Endocrine therapy remains the backbone of systemic therapy in both early and advanced stage hormone receptor positive breast cancer. Metastatic breast cancer is not curable however, and virtually all patients will eventually develop resistance to both tamoxifen and the aromatase inhibitors. Fulvestrant is a new pure estrogen receptor antagonist which binds with high affinity to the estrogen receptor and inhibits receptor dimerization, which leads to downregulation of cellular estrogen and progesterone receptor levels. In a recent multicenter study of fulvestrant, the clinical benefit rate to fulvestrant and exemestane in their target population was 32%, indicating the need to individualize therapy to identify patients who might benefit from this treatment. Currently, there are no predictors to identify the two thirds of non-responders in the target population of patients who are prescribed fulvestrant following prior hormonal agents. [18F]Fluoroestradiol ([18F]FES) is an imaging agent which allows the non-invasive assessment of estrogen receptor (ER) expression in breast cancers, allowing quantitative assessment of radiolabeled estrogen uptake at tumor sites and the ability to assess receptor expression heterogeneity across metastatic sites. The main purpose of this study is to prospectively assess the potential of [18F]FES PET/CT imaging to predict the benefit of administering fulvestrant in women with recurrent or metastastic breast cancer who have progressed following treatment with aromatase inhibitors and/or tamoxifen. The study hypotheses are: 1) High [18F]FES uptake at the baseline scan in known tumor sites is predictive of clinical benefit to fulvestrant therapy, while low [18F]FES uptake in some or all active tumor sites is predictive of fulvestrant therapy failure 2) Limited blockage/downregulation of [18F]FES uptake after 3 months of fulvestrant therapy is predictive of treatment failure. To assess these hypotheses we will conduct a prospective phase II cohort study to determine whether [18F]FES uptake at baseline and/or after reaching pharmacological steady-state of fulvestrant therapy can predict clinical benefit to this drug. The accrual plan is 100 patients over 2 years. PUBLIC HEALTH RELEVANCE: Fulvestrant is a relatively new drug that can be used to treat patients with advanced breast cancer once they have become resistant to other forms of therapy. Since only around 30% of patients will benefit from fulvestrant therapy, we propose to determine whether a state- of-the art imaging technique can predict which patients will respond. Success would benefit breast cancer patients by allowing physicians to make better decisions about who should be treated with fulvestrant, and who may respond better to alternative treatments.